Low vitamin D levels have been associated with increased mortality, but randomized trials in participants with severe vitamin D deficiencies are lacking. This study used nonlinear Mendelian randomization to assess genetic evidence for the role of low vitamin D status in mortality.
Abstract
Background:
Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking.
Objective:
To assess genetic evidence for the causal role of low vitamin D status in mortality.
Design:
Nonlinear Mendelian randomization analyses.
Setting:
UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010.
Participants:
307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data.
Measurements:
Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020.
Results:
There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L.
Limitations:
Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate.
Conclusion:
Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels.
Primary Funding Source:
National Health and Medical Research Council.
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Author, Article, and Disclosure Information
Joshua P. Sutherland,
Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia (J.P.S.)
Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia (A.Z., E.H.).
Acknowledgment: The authors thank all UK Biobank participants involved, as well as Dr. Anwar Mulugeta (University of South Australia) for support in data management.
Financial Support: By grant 11123603 from the National Health and Medical Research Council. Mr. Sutherland's studentship is funded by an Australian Research Training Program Scholarship.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-3324.
Reproducible Research Statement: Study protocol: Not available. Data set and statistical code: This research has been conducted using the UK Biobank resource under application 20175. All data and code will be available to approved users on application to the UK Biobank.
Corresponding Author: Elina Hyppönen, PhD, Australian Centre for Precision Health, University of South Australia, c/o South Australian Health and Medical Research Institute, GPO Box 2471, Adelaide, SA 5001, Australia; e-mail, Elina.
Author Contributions: Conception and design: E. Hyppönen.
Analysis and interpretation of the data: E. Hyppönen, J.P. Sutherland, A. Zhou.
Drafting of the article: E. Hyppönen, J.P. Sutherland, A. Zhou.
Critical revision for important intellectual content: E. Hyppönen, A. Zhou.
Final approval of the article: E. Hyppönen, J.P. Sutherland, A. Zhou.
Provision of study materials or patients: E. Hyppönen.
Statistical expertise: E. Hyppönen, A. Zhou.
Obtaining of funding: E. Hyppönen.
Administrative, technical, or logistic support: E. Hyppönen, J.P. Sutherland.
Collection and assembly of data: J.P. Sutherland, A. Zhou.
This article was published at Annals.org on 25 October 2022.
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